SX-576 is a small molecule CXCR1/2 antagonist that potently blocks the migration of neutrophils to sites of injury and/or inflammation. SX-576 is being developed as a potential therapeutic for the treatment of pulmonary inflammatory diseases, such as bronchopulmonary dysplasia (BPD) and chronic obstructive pulmonary disease (COPD). In this study, the pharmacokinetic properties of SX-576 will be optimized through chemical structure modification and formulation development. The new analogs and formulations will be evaluated for activity in isolated human neutrophils, and for improved oral bioavailability in pharmacokinetic studies. A preclinical candidate will be selected and evaluated in a rat model of pulmonary inflammation. A process for the large scale preparation and formulation of the preclinical lead compound will be developed, followed by toxicology studies to assess its safety. At the conclusion of this study, the necessary information for an Investigational New Drug (IND) application for clinical evaluation in humans will have been collected. In summary, the successful completion of this study would advance a potential new treatment for pulmonary inflammatory diseases, thereby advancing the mission of the NIH to lessen the burdens of illness in our society. PUBLIC HEALTH RELEVANCE: Pulmonary inflammatory diseases such as bronchopulmonary dysplasia (BPD) and chronic obstructive pulmonary disease (COPD) affect more than 12 million people in the U.S., and represent a significant burden to public health. This Phase II competing renewal would advance a novel anti-inflammatory drug towards clinical evaluation in patients suffering from pulmonary inflammatory disease.